Transcript Improving Outcome in Ovarian Cancer Trials and Tribulations

NEW AGENTS ON THE HORIZON: IMPLICATIONS FOR
PHASE I, II & III TRIALS
DNA Repair and PARP inhibitors
Carol Aghajanian, Nicoletta Colombo & Amit Oza
Acknowledgements: Stan Kaye and AZ for slides
Amit M. Oza
Professor of Medicine,
Princess Margaret Hospital,
University of Toronto
Co-Chair Gynecology, NCIC CTG
Types of DNA damage and repair
Type of
damage:
Singlestrand
breaks
(SSBs)
Doublestrand
breaks
(DSBs)
Bulky
adducts
O6alkylguanine
Insertions
& deletions
Mismatch
repair
Repair
pathway:
Base
excision
repair
Poly
Repair
ADP
enzymes:
Ribose
Polymer
ase
Recombinational
repair
HR
NHEJ
ATM
DNA-PK
BRCA
Nucleotideexcision
repair
XP,
MSH2,
poly- MLH1
merases
Direct
reversal
AGT
PARP-1 is a key enzyme involved in the repair of singlestrand DNA breaks
DNA damage
PAR chains
are
degraded
via PARG
PARP
Binds directly
to SSBs
Repaired
DNA
NAD+
Nicotinamide
+pADPr
Repair
enzymes
PAR
Once bound to damaged
DNA, PARP modifies itself
producing large branched
chains of PAR
Inhibiting PARP-1 increases double-strand DNA damage
DNA SSB
PNK 1
XRCC1
pol β
LigIII
PARP
Inhibition of
PARP-1
prevents
recruitment of
repair factors
to repair SSB
Replication
(S-phase)
DNA DSB
Selective effect of PARP-1 inhibition on cancer cells
with BRCA1 or BRCA2 mutation
DSB in DNA
Normal cell
DSB
repaired
effectively
via HR
pathway
Cell
survival
BRCA-deficient cancer cell
Deficient HR pathway
– DSB not repaired
Cancer cell
death
Tumour Selective Synthetic Lethality
HR deficient
e.g. BRCA1/2-/-
Normal or
heterozygote
for HR defect
DNA DAMAGE
HR NHEJ SSA BER NER etc
x
PARPi
DNA DAMAGE
HR NHEJ SSA BER NER etc
x
x
PARPi
Lethality
Error prone repair
Genomic instability
Cell death
RESPONSE TO AZD 2281, Parp inhibitor OLAPARIB BY
PLATINUM-FREE INTERVAL
Total
Platinum
sensitive
Platinum
resistant
Platinum
refractory
46
10
25
11
Responders by RECIST
13 (28%)
5 (50%)
8 (32%)
0 (0%)
Responders by GCIG
CA125
18 (39%)
8 (80%)
8 (32%)
2 (18%)
Responders by either
RECIST or GCIG criteria
21 (46%)
8 (80%)
11 (44%)
2 (18%)
SD (> 4 cycles)
9 (15%)
1 (10%)
4 (16%)
1 (9%)
31 (10-96)
31 (16-96)
29 (10-84)
39 (27-51)
No. of evaluable patients
Median duration of
response in weeks
(range)
Strong family history
Ovarian BRCA123 mm/-
Ovarian BRCA1-/-
12 mm
6.8 mm
Breast BRCA?
21.05.07
03.04.07
6.5 mm
3 mm
Platinum-free interval (months)
CORRELATION OF PLATINUM SENSITIVITY WITH
RESPONSE TO OLAPARIB
24
Resistant
Sensitive
Refractory
18
12
6
0
CR/PR
SD >4 months
PD
SINGLE AGENT TREATMENT WITH
OLAPARIB

Well tolerated oral therapy not associated with the typical
toxicities of chemotherapy

Clear evidence of beneficial tumour response in BRCA
mutated ovarian cancer patients
• 46% (21/46 pts) response rate (RECIST or GCIG CA125)
• 15% meaningful disease stabilisation
• Total clinical benefit rate of 61%
• Median response duration: 8 m

Randomized trials now underway
POTENTIAL OF PARP INHIBITOR (SINGLE
AGENT) IN SPORADIC OVARIAN CANCER
Question:
Answer:
Therefore:
What proportion of ovarian cancer patients will
have BRCA1/2 dysfunction, either due to mutation
of either gene or for other reasons, e.g.
methylation of this or related genes?
• approx 15% of sporadic ovarian cancers have
mutation of either gene; in serous histological
subtypes, proportion is 18%
• approx 15-20% more cases have BRCA
dysfunction, through methylation, etc.
• approx 10% have FANCF methylation
potentially half the cases of serous ovarian ca
could benefit from targeted single agent treatment
- how can these be identified?
Phase I-II studies

Phase I:


Phase II:


Combination with - platinum, topotecan
Single agent BRCA +/-
Randomized Phase II/III


Post chemo consolidation/maintenance
Combination/maintenance

Carbo/taxol +/- Parp inhibitor
Parp Inhibition

Compelling efficacy data in hereditary ovarian cancer
patients

Studies in hereditary ovarian cancer.

High grade serous histology – “BRCAness”


Without BRCA mutations
Combination studies

Chemotherapy

Targeted agents
PARP Inhibitors in Clinical Trials
Agent
Company
Strategy
AG014699
Pfizer
Combination*
KU59436
AstraZenecaKudos
Single
Oral
ABT-888
Abbott
Single
Oral
BSI-201
BiPar
Single
Combinations
IV
INO-1001
InotekGenentech
Combination*
IV
MK
Merck
Single agent and
combination
Oral
GPI 21016
MGI Pharma
Combination*
Oral
Adapted Ratnam K, Low JA Clin Cancer Res 2007;13: 1383-1388
Administration
IV
FURTHER DEVELOPMENT OF OLAPARIB - 1
Patients with
advanced
ovarian cancer
with BRCA-1 or
2 mutations,
relapsed within
12 months of
platinum-based
chemotherapy
R
A
N
D
O
M
I
S
E
olaparib 400 mg bd cont
olaparib 200 mg bd cont
caelyx/doxil 50 mg/m2 q4 weekly
n = 90, recruitment complete
primary end point = PFS
statistical analysis: combined olaparib arms vs caelyx/doxil,
aimed at detecting incr. in PFS from 4 m
to 7.3 m (HR 0.55, 80% power)
FURTHER DEVELOPMENT OF OLAPARIB - 2
Patients with
serous ovarian
cancer,
responding to 2nd
or 3rd line
platinum-based
chemo, with
CR/PR
(penultimate
treatment-free
interval >6 m)
R
A
N
D
O
M
I
S
E
olaparib 400 mg bd
until PD
placebo until PD
n = 250
- BRCA mutation not necessary
Primary end point: progression-free survival
Recruitment now underway
PATIENT SELECTION FOR SINGLE AGENT
Predictive biomarker:
•
immunohistochemistry, with BRCA 1/2
antibodies
•
functional (ex vivo) test for loss of HR (RAD
51 foci-formation)
•
molecular signature (gene array)
and/or: background of • repeated response to
platinum-based chemo
• prolonged survival (>5 yrs)
• serous histology